The Ghaffari laboratory investigates mechanisms that regulate blood stem and progenitor cell formation that are implicated in the pathophysiology of blood disorders. We have been addressing these questions by focusing on FOXO family of transcription factors, which are key regulators of stress resistance and implicated in enhancing human longevity (FOXO3). In our studies we apply genetic tools and biochemistry to investigate the biology of mouse and human cells and the pathophysiology of various mouse models of human blood disorders.

In carrying this work forward we have set up multiple collaborations with investigators at Mount Sinai and elsewhere. Several projects deriving from the line of work described here are available to PhD and MD/PhD students at Mount Sinai.

Hematopoiesis, Hematopoietic Stem Cells and Erythropoiesis

Blood-forming stem cells have unique properties that enable them to live a long life and regenerate blood constantly. The well-being of blood-forming stem cells throughout life is essential for maintaining a healthy life by producing billions of red and white blood cells every day in humans. With aging this regenerative capacity declines which compromises optimum blood production and might also lead to blood malignancies whose incidence increases with age. The primary goal of our laboratory is to dissect the regulatory pathways that maintain the health of blood-forming stem and progenitor cells throughout life. We hope this knowledge will eventually lead to the identification of specific targets and/or development of novel tools that could be used in the clinic to improve therapy and/or to produce healthy blood-forming stem cells in a dish for bone marrow transplantation. In these efforts, we have identified the transcription factor FOXO3 and its regulatory network as critical regulators of blood-forming stem cells and their production of red blood cells.

Erythropoiesis, Red Blood Cells and FOXO3

Erythropoiesis is the process of making red blood cells (RBCs) from hematopoietic progenitor cells. RBCs carry oxygen and travel throughout the body to oxygenate all tissues. Anemia or reduced capacity of RBCs to carry oxygen constitutes a major health problem associated with many disorders. In response to loss or reduced production of RBCs, blood-forming stem and progenitor cells are activated to produce RBCs. RBC production is dependent mainly on erythropoietin, a hormone that is produced when oxygen levels are low. We found FOXO3, a protein that regulates a response to oxygen levels and whose function is partly controlled by erythropoietin, as key to physiologicalregulation of red blood cell maturation and production and the regulation of harmful consequences of oxygen metabolism (oxidative stress) during this process. Our work suggests that enhancing FOXO3 function might increase RBC production in a dish. We are currently evaluating whether some of FOXO3 targets might recapitulate its function and also increase RBC formation in a dish.

Dormancy is a fundamental property of most adult stem cells. The regeneration capacity of adult blood-forming stem cells is tightly linked to their dormancy, a property that requires the transcription factor FOXO3. The maintenance of stem cell dormancy requires balanced metabolism and mitochondrial function. Our work indicates that FOXO3 is required for mitochondrial metabolism in blood-forming stem cells. We have devised a new approach to investigate stem cell functions. Using this novel approach and other tools we have acquired or developed, we are delving deep into mitochondrial metabolism, its regulation of blood-forming stem cells, and the role of FOXO3. We are also using these tools to dissect the generation of leukemic stem cells and the potential contribution of FOXO3 to this process. Our hope is that these combined approaches will enhance our ability to identify molecules that interfere with abnormal mitochondrial metabolism that might eventually be used therapeutically to modulate stem cell function.

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Dr. Ghaffari has not yet completed reporting of Industry relationships.

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